Gene-by-Gene Interactions and Lung Fluid Balance in Patients with Heart Failure

描述（由申请人提供）：失代偿性心力衰竭挑战肺部维持体液平衡的能力，并可导致肺泡泛洪和死亡；然而，并非所有失代偿性心力衰竭患者都发生肺水肿，尽管临床特征相似，这表明遗传影响了该人群对肺水肿的易感性。在肺中，肺泡Na+和液体清除主要由上皮Na+通道（ENaC）的活性调节。ENaCs的活性和数量受2肾上腺素能受体（ADRB2s）调控。内源性（肾上腺素）或外源性激动剂刺激ADRB2s可增加肺泡液清除率。因此，有三种关键蛋白参与肺泡液清除：ADRB2s、ENaCs和肾上腺素。在编码ADRB2 （ENaC的α亚基）和苯乙醇胺N-甲基转移酶（PNMT，将去甲肾上腺素转化为肾上腺素）的基因中存在常见的功能变异。目前还不清楚这些基因对心力衰竭患者有什么影响。我们的长期目标是根据遗传信息确定适当的治疗干预措施，以改善疾病中离子和肺液的调节。本提案的目的是确定遗传变异对肺Na+和液体处理的影响，这可能具有重要的临床应用，特别是在肾上腺素能驱动升高的心力衰竭患者中。我们的中心假设是ADRB2、ENaC和PNMT的遗传变异会影响基线肺液和肺液对激动剂的清除率。提出这项研究的基本原理是，确定这些基因如何调节心力衰竭中的肺液，将允许当前治疗的个性化，以及利用替代疗法来减少心力衰竭中肺水肿的易感性。这一建议意义重大，因为我们将探索刺激2-肾上腺素能受体对肺液平衡的治疗效果，以及遗传变异如何影响这种治疗反应。这将增加对用于降低心衰患者肺水肿风险的特定疗法的理解。这项研究具有创新性，因为我们将测试ADRB2、ENaC和PNMT基因变异（尚未在HF患者中一起探索）对HF患者肺离子和液体调节的影响，我们正在确定多个基因如何共同作用以影响HF患者肺液体平衡，最后，我们最近开发了一种评估肺离子和液体变化的新技术，我们将与现有方法相结合，扩大可用于评估肺水变化的技术。

DESCRIPTION (provided by applicant): Decompensated heart failure challenges the ability of the lungs to maintain fluid homeostasis and can result in alveolar flooding and death; however, not all patients with decompensated heart failure develop pulmonary edema, despite similar clinical characteristics, suggesting a genetic influence on susceptibility to pulmonary edema in this population. In the lungs, alveolar Na+ and fluid clearance are primarily regulated by the activity of epithelial Na+ channels (ENaC). The activity and number of ENaCs are regulated by ¿2 adrenergic receptors (ADRB2s). Stimulation of the ADRB2s by an endogenous (epinephrine) or exogenous agonist increases alveolar fluid clearance. Therefore, there are three key proteins involved in alveolar fluid clearance: ADRB2s, ENaCs, and epinephrine. There are common functional variants in the genes that encode the ADRB2, the alpha subunit of the ENaC, and phenylethanolamine N- methyltransferase (PNMT, which converts norepinephrine to epinephrine). It remains unclear what effects of these genes will be on patients with heart failure. Our long term goal is to determine appropriate therapeutic interventions for improving ion and lung fluid regulation in disease based on genetic information. The objective in this proposal is to determine the influence of genetic variation on lung Na+ and fluid handling, which is likely to have significant clinical applications, particularly in patients with heart failure who have an elevated adrenergic drive. Our central hypothesis is that genetic variation of the ADRB2, ENaC, and PNMT will influence baseline lung fluid and lung fluid clearance in response to a ¿-agonist. The rationale for the proposed research is that determining how these genes regulate lung fluid in heart failure will allow for personalization of current therapy as well as utilization of alternative therapies to reduce the susceptibility of pulmonary edema in heart failure. This proposal is significant because we will explore the therapeutic effects of stimulation of the ¿2-adrenergic receptors on lung fluid balance, and how genetic variation can influence this therapeutic response. This will add to the understanding of specific therapies used to reduce the risk of pulmonary edema in patients with HF. The research proposed is innovative because we will be testing the influence of genetic variation of ADRB2, ENaC and PNMT (which have not been explored together in patients with HF) on lung ion and fluid regulation in HF, we are determining how multiple genes interact together to influence lung fluid balance in patients with HF, and, finally, we have recently developed a new technique to assess lung ion and fluid changes which we will couple with existing methods to expand techniques that can be used to assess changes in lung water. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because complications from heart failure (HF), including symptoms of pulmonary edema, are the number one reason for hospital admissions in the United States. Understanding the genetic influence to this susceptibility is key for therapeutic progress in HF. Thus, the proposed research is relevant to the NIH mission in that it will translate clinical research obtained in a laboratory setting in HF patients to clinical practice.